Method for Treating Diabetes

ABSTRACT

This application is directed to the use of steroid compounds for the selective inhibition of the enzyme PTP1B in a mammal for the treatment of diabetes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/970,467, filed Sep. 6, 2007, which is incorporated by reference inits entirety.

FIELD OF THE INVENTION

This application is directed to the use of steroid compounds for theselective inhibition of the enzyme PTP1B in a mammal for the treatmentof diabetes.

BACKGROUND OF THE INVENTION

Several aminosterol compounds have been isolated from the liver of thedogfish shark, Squalus acanthias. One of these compounds has beendesignated as 1436, the structure of which is shown in FIG. 1. Compound1436 has been previously described in, e.g., U.S. Pat. Nos. 5,763,430;5,795,885; 5,847,172; 5,840,936 and 6,143,738, each of which isincorporated by reference in its entirety, and has been shown to inhibitweight gain and suppress appetite, which leads to weight loss in animalmodels.

Diabetes is a major medical problem in the United States andincreasingly so in the rest of the developed world. Type II diabetes inparticular is caused primarily by the effects of a sedentary life styleand a fat-rich diet. The diabetic individual is susceptible to medicalproblems directly related to his disease such as elevated serumcholesterol, high blood pressure, congenital obesity syndromes(including congenital leptin, pro-opiomelanocortin (POMC) andmelanocortin-4 receptor (MC4R) deficiencies), and sleep apnea,especially in pickwickian syndrome. In addition, the accumulation of fatin the liver can progress to nonalcoholic steatohepatitis and cirrhosis.Another problem for obese diabetic individuals is an increased risk inany surgery that must cut through thick layers of fatty tissue that arehighly vascularized and therefore prone to hemorrhage. Necessary surgeryis frequently postponed until this diabetic patient can lose sufficientweight to make the risk of the operation acceptable.

Insulin is an important regulator of different metabolic processes andplays a key role in the control of blood glucose. Defects related toinsulin synthesis and signaling lead to diabetes mellitus. Binding ofinsulin to the insulin receptor (IR) causes rapid autophosphorylation ofseveral tyrosine residues in the intracellular part of the beta-subunit.Three closely positioned tyrosine residues (the tyrosine-1150 domain)must be phosphorylated to obtain maximum activity of the insulinreceptor tyrosine kinase (IRTK), which transmits further signals viatyrosine phosphorylation of other cellular substrates, including insulinreceptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2).

Protein phosphorylation is a well-recognized cellular mechanism fortransducing and regulating signals during different stages of cellularfunction (see, e.g., Hunter, Phil, Trans. R. Soc. Lond. B. 353: 583-605(1998); Chan et al., Annu. Rev. Immunol. 12: 555-592 (1994); Zhang,Curr. Top. Cell. Reg. 35: 21-68 (1997); Matozaki and Kasuga, Cell.Signal. 8: 113-119 (1996)). There are at least two major recognizedclasses of phosphatases: (1) those that dephosphorylate proteins thatcontain a phosphate group(s) on a serine or threonine moiety (termedSer/Thr phosphatases or dual specificity phosphatases or DSPs) and (2)those that remove a phosphate group(s) from the amino acid tyrosine(termed protein tyrosine phosphatases or PTPases or PTPs).

Several studies clearly indicate that the activity of theauto-phosphorylated IRTK can be reversed by dephosphorylation in vitro(reviewed in Goldstein, Receptor 3: 1-15 (1993)) with thetri-phosphorylated tyrosine-1150 domain being the most sensitive targetfor PTPases. This tri-phosphorylated tyrosine-1150 domain appears tofunction as a control switch of IRTK activity and the IRTK appears to betightly regulated by PTP-mediated dephosphorylation in vivo (Faure etal., J. Biol. Chem. 267: 11215-11221 (1992)).

PTP has been identified as at least one of the major phosphatasesinvolved in IRTK regulation through studies conducted both in vitro(Seely et al., Diabetes 45: 1379-1385 (1996)) and in vivo using PTP1Bneutralizing antibodies (Ahmad et al., J. Biol. Chem. 270: 20503-20508(1995)). Three independent studies have indicated that PTP knock-outmice have increased glucose tolerance, increased insulin sensitivity anddecreased weight gain when on a high fat diet (Elchebly et al., Science283: 1544-1548 (1999), Klaman et al., Mol. Cell. Biol. 20: 5479-5489(2000), and Bence et al., Nature Med (2006)). Overexpression or alteredactivity of tyrosine phosphatase PTP1B can contribute to the progressionof various disorders, including insulin resistance and diabetes (Ann.Rev. Biochem. 54: 897-930 (1985)). Furthermore, there is evidence whichsuggests that inhibition of protein tyrosine phosphatase PTP istherapeutically beneficial for the treatment of disorders such as type Iand II diabetes, obesity, autoimmune disorders, acute and chronicinflammation, osteoporosis and various forms of cancer (Zhang Z Y etal., Expert Opin. Investig. Drugs 2: 223-33 (2003); Taylor S D et al.,Expert Opin. Investig. Drugs 3:199-214 (2004); J. Natl. Cancer Inst. 86:372-378 (1994); Mol. Cell. Biol. 14: 6674-6682 (1994); The EMBO J. 12:1937-1946 (1993); J. Biol. Chem. 269: 30659-30667 (1994); andBiochemical Pharmacology 54: 703-711(1997)). Agents that inhibitphosphatase activity and thereby inhibit dephosphorylation of theinsulin signaling pathway, increase whole-body insulin sensitivity. Thisis therapeutically beneficial in treatment of insulin resistanceassociated with Type II diabetes and obesity.

In addition, it has been shown (Bence K K et al., Nat Med 8:917-24(2006)) that neuronal PTP1B in the brain regulates body weight,adiposity and leptin action. Therefore, if a PTP1B inhibitor can crossthe blood brain barrier it will not only sensitize the effect of insulinbut also result in weight loss an added benefit in the treatment of typeII diabetes and in addition the treatment of obesity and itscomplications.

There is also reported insulin resistance in Type I diabetes for whichagents with PTP1B inhibitory activity would be a useful therapeutic. Aninsulin sensitizing agent in early type I diabetes or in a pre-diabeticstatue might delay the onset of diabetes by increasing the sensitivityto insulin and thereby reducing the requirement for over-secretion ofinsulin from remaining insulin-producing beta-cells in the pancreas,i.e. sparing these cells from subsequent “burn-out” and death. It hasalso been shown (Jiang Z X and Zhang Z Y, Cancer Metastasis Rev.2:263-72 (2008)) that inhibitors of PTP1B can prevent the growth oftumors and therefore be useful for the treatment of cancer.

The PTPase family of enzymes can be classified into two subgroups: (1)intracellular or nontransmembrane PTPases and (2) receptor-type ortransmembrane PTPases. Most known intracellular type PTPases contain asingle conserved catalytic phosphatase domain consisting of 220-240amino acid residues. The regions outside the PTPase domains are believedto play important roles in localizing the intracellular PTPasessubcellularly (Mauro, L. J. and Dixon J. E., TIBS 19: 151-155 (1994)).The first of the intracellular PTPases to be purified and characterizedwas PTP1B (Tonks et al., J. Biol. Chem. 263: 6722-6730 (1988)). Otherexamples of intracellular PTPases include (1) T-cell PTPase (TCPTP)(Cool et al., Proc. Natl. Acad. Sci. USA 86: 5257-5261 (1989)), (2)neuronal phosphatases STEP (Lombroso et al., Proc. Natl. Acad. Sci. USA88: 7242-7246 (1991)), (3) PTP1C/SH-PTP1/SHP-1 (Plutzky et al., Proc.Natl. Acad. Sci. USA 89: 1123-1127 (1992)), (4) PTP1D/Syp/SH-PPT2/SHP-2(Vogel et al., Science 259: 1611-1614 (1993); Feng et al., Science 259:1607-1611(1993)).

Receptor-type PTPases consist of (a) a putative ligand-bindingextracellular domain, (b) a transmembrane segment, and (c) anintracellular catalytic region. The structure and sizes of the putativeligand-binding extracellular domains of receptor-type PTPases are quitedivergent. In contrast, the intracellular catalytic regions ofreceptor-type PTPases are very homologous to each other and to theintracellular PTPases. Most receptor-type PTPases have two tandemlyduplicated catalytic PTPase domains. The first PTPase receptor subtypesidentified were (1) CD45 (Ralph, S. J., EMBO J. 6: 1251-1257 (1987)) and(2) LAR (Streuli et al., J. Exp. Med. 168:1523-1530 (1988)). Since then,many more receptor subtypes have been isolated and characterized,including, e.g., PTPalpha, PTPbeta, PTPdelta, PTPepsilon and PTPxi.(Krueger et al. EMBO J. 9: 3241-3252 (1990)).

Although agents have been identified for use as PTP1B inhibitors, suchas the heteroaryl- and aryl-amino acetic acids described in WO 01/19831,WO 01/19830, and WO 01/17516, these agents do not exhibit separation ofthe inhibitory activity between PTP1B and TCPTP. Furthermore, because ofthe potential immunosuppressive effects resulting from inhibiting TCPTP,selective inhibition of PTP1B over TCPTP would make such agents moresuitable for drug development as they could diminish or eliminateundesired side effects resulting from such nonselectivity.

Therefore, there is a need for a drug that can safely treat diabetes bythe selective inhibition of PTP1B. In addition, if neuronal PTP1B isinhibited rapid weight loss can be induced in obese individuals thusalso treating the effects of obesity, prevent neurodegeneration orAlzheimer's. A drug of this type would also be useful for the treatmentof complications due to obesity, obesity in type II diabetes, high serumcholesterol, sleep apnea (especially in pickwickian syndrome),nonalcoholic steatohepatitis and surgery for obese patients. Finally, aPTP1B inhibitor could also be useful for the treatment of cancer.

SUMMARY OF THE INVENTION

The present invention relates to various aminosteroids which inhibitprotein phosphatase IB (PTPIB). The invention also relates tocompositions which contain these aminosteroids, and methods of their useto treat diabetes in mammals, particularly humans.

One aspect of the invention relates to steroid compounds that areinhibitors of the enzyme PTP1B of the following formula, or apharmaceutically acceptable salt thereof:

wherein:R₁═—NH(CH₂)₁₋₄—NH—R₆ or —OH or ═O or H or piperazine or aminopiperidine;R₆═—(CH₂)₁₋₄—NH—R₇ or C₁-C₅ alkyl or phenyl or H;R₇═—(CH₂)₁₋₄—N—R₈;R₈═C₁-C₅ alkyl or benzyl or benzyl with 1-3 R₉ groups or H;R₉═—OH or —OCH₃ or —C₁-C₅ alkyl;

R₂═—OH or H; R₃═—OH or H; R₄═—OH or H; R₅=

or C₁-C₅ alkyl;R₁₀═H or C₁-C₅ alkyl.

Another aspect of the invention is a compound selected from thecompounds listed in Table 1, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a pharmaceutical compositioncomprising a compound listed in Table 1 and a diluent or carrier.

Another aspect of the invention is a method of treating or preventingdiabetes in a mammal, particularly a human, comprising administering tosaid mammal a therapeutically effective amount of a compound of theabove formula or a compound listed in Table 1.

Another aspect of the invention is a method for treating a disorder in amammal mediated by inhibition of protein tyrosine phosphatase PTP1Bcomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the above formula or a compound ofTable 1.

In exemplary embodiments, the disorder treated by administration of acompound of the above formula or a compound of Table 1 includes, but isnot limited to, obesity in type II diabetes, high serum cholesterol,sleep apnea and nonalcoholic steatohepatitis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows that MSI-1701 and 1873 treated ob/ob mice have lowerfasting blood glucose levels compared to saline treated controls.

FIG. 2 shows a graph of the glucose tolerance test that produced thedata in FIG. 3.

FIG. 3 shows that MSI-1701 and 1873 treated ob/ob mice respondsignificantly faster in a glucose tolerance test than the saline treatedcontrols.

FIG. 4 shows that MSI-1436 can increase the level of insulin stimulatedtyrosine phosphorylation of IRβ in the rat hypothalamus.

DETAILED DESCRIPTION OF THE INVENTION

The compounds listed in Table 1 are intended to include allpharmaceutically acceptable salts of the listed compounds. In addition,where the stereochemistry at any given carbon atom is undefined, it isintended that each individual stereoisomer is encompassed as well as theracemic mixture.

The aminosteroids of the invention may be administered alone or as partof a pharmaceutical composition. Pharmaceutical compositions for use invitro or in vivo in accordance with the present invention may beformulated in a conventional manner using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen. Examples of carriers or excipientsinclude, but are not limited to, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin and polymerssuch as polyethylene glycols.

In addition to carriers, the pharmaceutical compositions of theinvention may also optionally include stabilizers, preservatives and/oradjuvants. For examples of typical carriers, stabilizers and adjuvantsknown to those of skill in the art, see Remington: The Science andPractice of Pharmacy, Lippincott, Williams & Wilkins, 21^(st) ed.(2005), which is incorporated by reference in its entirety.

Optionally, other therapies known to those of skill in the art may becombined with the administration of the aminosteroids of the invention.More than one aminosteroid may be present in a single composition.

In vivo administration of the aminosteroids of the invention can beeffected in one dose, multiple doses, continuously or intermittentlythroughout the course of treatment. Doses range from about 0.01 mg/kg toabout 10 mg/kg, preferably between about 0.01 mg/kg to about 1 mg/kg,and most preferably between about 0.1 mg/kg to about 1 mg/kg in singleor divided daily doses. Methods of determining the most effective meansand dosages of administration are well known to those of skill in theart and will vary with the composition used for therapy, the purpose ofthe therapy, the target cell being treated and the subject beingtreated. Single or multiple administrations can be carried out with thedose level and pattern being selected by the treating physician.

Pharmaceutical compositions containing the aminosteroids of theinvention can be administered by any suitable route, including oral,rectal, intranasal, topical (including transdermal, aerosol, ocular,buccal and sublingual), parenteral (including subcutaneous,intramuscular, intravenous), intraperitoneal and pulmonary. It will beappreciated that the preferred route will vary with the condition andage of the recipient, and the disease being treated.

For oral administration, the aminosteroids of the invention can beformulated readily by combining them with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, alginicacid or a salt thereof, such as sodium alginate.

For administration by inhalation, the aminosteroids of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The aminosteroids can be formulated for parenteral administration byinjection, e.g., bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as buffers,bacteriostats, suspending agents, stabilizing agents, thickening agents,dispersing agents or mixtures thereof.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions. In apreferred embodiment, the aminosteroids of the invention are dissolvedin a 5% sugar solution, such as dextrose, before being administeredparenterally.

For injection, the aminosteroids of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

The aminosteroids may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

The aminosteroids may also be combined with at least one additionaltherapeutic agent.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following workingexamples therefore, specifically point out preferred embodiments of thepresent invention, and are not to be construed as limiting in any waythe remainder of the disclosure.

EXAMPLES Example 1 Inhibition of PTP1B by Steroid Analogues

The steroid analogues were tested for inhibition against thecommercially available full length tyrosine phosphatase PTP1B. Theability of each analogue to inhibit the activity of PTP1B was measuredin the presence of 10 μM of the steroid analogue. The assay usespara-nitro-phenyl phosphate (pNPP), a non-specific substrate to assessphosphatase activity. Phosphatase activity was based on the ability ofPTP1B to catalyze the hydrolysis of pNPP to p-nitrophenol (pNP). Theactivity was measured using a single point spectrophometric absorbanceat 405 nm (the absorbance of the chromogenic product, para-nitrophenol(pNP). The percent inhibition of tyrosine phosphatase activity by thesteroid analogues was determined by the fractional response of pNPformation in the presence of inhibitor over the maximal response pNPformation observed in the absence of inhibitor. The results of theseassays are shown in Table 1, column C and show many analogues that causegreater than 50% inhibition at 5 μM concentration.

Example 2 Inhibition of TCPTP by Steroid Analogues

The steroid analogues were also tested for their ability to inhibit thetyrosine phosphatase TCPTP as an indication of their potential toxicityby the inhibition of the immune response. The TCPTP inhibition assay wasdone in the same manner as the PTP1B assay except full length TCPTP wasused as the enzyme and the inhibitor was at a concentration of 200 μM.The results of the TCPTP inhibition assays are shown in Table 1, columnD and show three compounds that inhibit TCPTP less than 50% even at a 20fold greater concentration.

Example 3 Effect of Steroid Analogues on Body Weight, Blood GlucoseLevels and the Oral Glucose Tolerance Test (OGTT) in the Diabetic Mouse

To determine in vivo efficacy of the steroid analogues a Db/db(Lepr^(db)) mouse model was used. Db/db mice are extensively used forscreening of antidiabetic agents. Db/db mice were treated with eithersaline or 5 or 10 mg/kg steroid analogue every 3 days for a total of 4doses via ip injection. Body weight, glucose tolerance and fasting bloodglucose levels were measured for each group during the study. Each grouphad at least an N of 4 animals. All reagents and lab animals arecommercially available.

Starting at study day 0, body weight measurements were taken every dayfor each group for up to 30 days. Percent change in body weight wascalculated as the fractional response of body weight on study day X overthe original body weight on study day 0. Animals displaying a reductionin body weight suggest that the steroid analogue inhibits neuronal PTP1Bas is shown for MSI-1436 in Example 4 below. Table 1, column G shows %change in body weight for some 1436 analogues. MSI-1431 is seen toproduce weight loss similar to 1436 but 1701 and 1873 able to inhibitPTP1B but do not produce weight loss.

On study day 13, all animal groups were fasted overnight. On study day14, 25 μL of whole blood was collected and analyzed for the glucoselevel (mg/dL) using a glucose analyzer. A significant reduction of FBGlevels compared to saline control is shown for MSI-1431, 1436, 1701,1814 and 1873 in FIG. 1 and Table 1, column D.

Also on study day 14, an OGTT was performed to assess glucose tolerance.At time 0, an oral glucose challenge (1.5 g/kg) was administered by oralgavage. At timepoints 0, 15, 30, 60, 90, 120 min post glucose load, 25μl of whole blood was withdrawn from the tail vein of the animal and theglucose level was measured using a glucose analyzer. The glucoseconcentration vs time was plotted (FIG. 2). Above baseline area underthe curve (ABAUC) of the glucose excursion time curve was determinedusing trapezoidal rule analyses. A significant reduction (p<0.05) inABAUC compared to saline control is shown for MSI-1431, 1436, 1701, 1814and 1873 in FIG. 3 and Table 1, column F.

Example 4 Effect of MSI-1436 on the Phosphorylation of IR-β in the RatHypothalamus

Male SD rats were divided into 8 groups with 4 rats per group. All ratswere fed ad libitum normal rodent chow and regular tap water. On Day 0,rats were dosed via intraperitoneal (i.p.) injection with 10 mg/kgMSI-1436 or 0.9% saline. Rats were fasted overnight from Day 0 to Day 1.On Day 1, animals were dosed i.p. with 0.9% saline or 100 U/kg ofinsulin. At 15 or 30 minutes post-dose (Day 1), animals were sacrificedand the hypothalamuses were harvested, transferred to 1.5 mL eppendorftubes, and frozen in liquid nitrogen. Samples were stored at −80° C.until further analysis. Hypothalamuses were pooled (3-4 per group) andhomogenized in 2-mL Wheaton vials and Dounce homogenizers in 1 mL oftissue extraction reagent plus phosphatase and protease inhibitors.Lysates were centrifuged for 10 minutes at 4° C. (14,000 rpm) and thesupernatants were transferred to new 1.5 mL eppendorf tubes. Lysates(500 μg) were immunoprecipitated for Insulin Receptor β overnight at 4°C. The samples were then bound to Protein A according to standardprotocols for 4 hours at 4° C. Samples were then washed 4× withRIPA/Empigen buffer and eluted in 4×LDS sample buffer. After elution,the samples were boiled at 95° C. for 5 min.

500 μg of total protein from each sample was loaded onto a 1.5 mm 4-12%Bis-Tris Novex gel and run at 175V for approximately 1 hr in 1×MOPSbuffer. The gel was transferred to nitrocellulose membrane overnight at4° C. and 10V in a Novex transfer blot apparatus and blocked thefollowing morning in 5% BSA for 1 hr at room temperature. Next, themembrane was incubated in anti-pTyr 4G10 primary antibody diluted to 1μg/μL in 1% BSA at room temperature for 2 hours. After 3 ten-minutewashes in TBST, the membrane was incubated at room temperature in goatanti-mouse secondary antibody diluted 1:80,000 in 1% BSA for 1 hr.Finally, the membrane was washed 3×10 min in TBST, 5×2 min in pico purewater, and developed using SuperSignal West Pico ECL reagent. Themembrane was exposed to film for various time points. Densitometricanalysis of the bands of interest was performed using ImageJ. The ratioof the pTyr-IRβ band to the IRβ band was computed in Excel and the foldchange in IR phosphorylation determined. The data indicates (FIG. 4)that treatment with MSI-1436 nearly doubles the amount ofphospho-Tyrosine found on insulin stimulated IR-13 in the hypothalamus.The assumption in this case is that MSI-1436 has crossed the blood brainbarrier into the hypothalamus and increased the amount ofphosphor-Tyrosine on IR-β by the inhibition on PTP1B.

TABLE 1 % % PTP1B TCPTP % Reduction in Change Inhibition InhibitionReduction OGTT Above in Body Compound Structure (5 μM) (200 μM) in FBGBaseline AUC Weight 1241

22 1255

43 1256

24 1271

26 1272

23 1303

58 83 1304

71 1317

43 1320

48  0 1321

28 1322

16 1336

67 1352

38 1370

66 44 1371

90  0 1409

 7 1413

53 1431

49 55 47 −7 1432

22 1436

72  0 64 83 −8 1433

27 1437

40 1448

65 1459

75 1466

85 1469

85 1470

59 1486

25 1487

44 1520

31 1521

50 1561

13 1562

20 1569

46 1597

70 1598

68 1678

22 1701

41 40 49  3 1718

19 1751

 6 1755

24 1768

13 1777

37 1783

36 1804

10 1805

17 1810

30 1811

 8 1812

37 1814

58 46 60 1830

18 1839

27 1873

63 41 47  4 1875

71 1876

43 1877

47 1888

81 1892

28 1893

16 1894

77 1909

41 1911

37 1913

38 1920

22 2347

27 2348

34 2349

27 2351

88 2352

76 2353

76 2354

43 2355

35 2356

23 2357

29 2358

24 2360

81 2361

82 2363

63 2364

61 2365

73 2367

78 2368

37 2369

93 2370

77 2371

55 2374

37 2375

59 2450

28 2451

 7 2459

17 2464

38 2465

10 2484

 5 2490

 7 2491

 9 2492

10 2492

10 2493

10 2494

 9 2495

 7 2496

10 2497

15 2498

13

1.-10. (canceled)
 11. A compound or pharmaceutically acceptable saltthereof selected from the group consisting of:


12. The compound of claim 11, where the compound is

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim11, where the compound is

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising the compound of claim 12 and a pharmaceuticallyacceptable diluent or carrier.
 20. A pharmaceutical compositioncomprising the compound of claim 13 and a pharmaceutically acceptablediluent or carrier.
 21. A pharmaceutical composition comprising thecompound of claim 14 and a pharmaceutically acceptable diluent orcarrier.
 22. A pharmaceutical composition comprising the compound ofclaim 15 and a pharmaceutically acceptable diluent or carrier.
 23. Apharmaceutical composition comprising the compound of claim 16 and apharmaceutically acceptable diluent or carrier.
 24. A pharmaceuticalcomposition comprising the compound of claim 17 and a pharmaceuticallyacceptable diluent or carrier.
 25. A pharmaceutical compositioncomprising the compound of claim 18 and a pharmaceutically acceptablediluent or carrier.